1. Field of the Invention
The present invention relates generally to the fields of molecular biology, hematology and oncology. More particularly, it concerns JAM-C-targeted antibodies and therapies and anti-cancer therapies with such antibodies.
2. Description of Related Art
Despite new treatment strategies, most mature B-cell lymphomas remain incurable. Evidence suggests that stromal cells in specialized tissue microenvironments, such as bone marrow (BM) and secondary lymphoid organs, are essential for disease progression. In fact, contact with stromal cells and the cytokines secreted by them favor viability, differentiation, proliferation, and retention of B cells and provide protection from conventional chemotherapy (Bertrand et al., 2000; Burger et al., 2009).
To enter lymphoid organs, B cells must adhere to endothelium and transmigrate across the endothelial barrier, thus chemokines and adhesion molecules are important in the homing of normal and malignant B cells and in lymphoma dissemination (Hartmann et al., 2009; Jin et al., 2006; Luster et al., 2005; Matsunaga et al., 2003; Mori et al., 2004; Okada and Cyster, 2006; Spiegel et al., 2004; Tavor et al., 2004). Both firm adhesion and transmigration across endothelial barriers depend on the ability of circulating cells to interact with endothelium through selectin ligands, integrins, or CD44. However, except CD44, these molecules are not involved in homing to the spleen.
Homing of circulating lymphocytes to secondary lymphoid organs is a multistep process, involving engagement of L-selectin, which mediates lymphocyte rolling along the luminal surface of HEVs, followed by activation of lymphocyte integrins and transmigration through the endothelial cell layer. Once inside lymphatic tissues, B and T lymphocytes migrate toward specific microenvironments, such as B-cell follicles and the paracortex, respectively. As HEVs are absent in spleen, lymphocytes enter this organ via the terminal branches of the central arterioles, which guide them into the marginal zone (Kraal et al., 1995; Miyasaka and Tanaka, 2004). In the bone marrow, migration of hematopoietic cells has been less well studied, although it is known that selectins and integrins are involved in homing to this organ (Cyster, 2003; Papayannopoulou, 2003) and that peripheral B lymphocytes enter through capillaries. Similar to normal B cells, the migration of malignant cells to specific lymphoid microenvironments constitutes a central aspect of B-cell lymphoma pathophysiology, and preventing lymphoma cells from reaching survival niches is important to stop tumor cell proliferation (Burger et al., 2009; Coupland, 2011).
It has been previously reported that B-cell homing to the spleen is integrin-independent, and that incubation of B cells with anti-alpha-4 integrin antibodies reduces homing only to BM and LNs (Hartmann et al., 2009; Lo et al., 2003; Koni et al., 2001; Berlin-Rufenach et al., 1999). Therefore, a new method to block homing of B cells to the spleen is needed.